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Prohibitin is a prognostic marker and therapeutic target to block chemotherapy resistance in Wilms' tumor

Item Type:Article
Title:Prohibitin is a prognostic marker and therapeutic target to block chemotherapy resistance in Wilms' tumor
Creators Name:Ortiz, M.V. and Ahmed, S. and Burns, M. and Henssen, A.G. and Hollmann, T.J. and MacArthur, I. and Gunasekera, S. and Gaewsky, L. and Bradwin, G. and Ryan, J. and Letai, A. and He, Y. and Naranjo, A. and Chi, Y.Y. and LaQuaglia, M. and Heaton, T. and Cifani, P. and Dome, J.S. and Gadd, S. and Perlman, E. and Mullen, E. and Steen, H. and Kentsis, A.
Abstract:Wilms' tumor is the most common type of childhood kidney cancer. To improve risk stratification and identify novel therapeutic targets for patients with Wilms' tumor, we used high-resolution mass spectrometry proteomics to identify urine tumor markers associated with Wilms' tumor relapse. We determined the urine proteomes at diagnosis of 49 patients with Wilms' tumor, non-Wilms' tumor renal tumors, and age-matched controls, leading to the quantitation of 6520 urine proteins. Supervised analysis revealed specific urine markers of renal rhabdoid tumors, kidney clear cell sarcomas, renal cell carcinomas as well as those detected in patients with cured and relapsed Wilms' tumor. In particular, urine prohibitin was significantly elevated at diagnosis in patients with relapsed as compared with cured Wilms' tumor. In a validation cohort of 139 patients, a specific urine prohibitin ELISA demonstrated that prohibitin concentrations greater than 998 ng/mL at diagnosis were significantly associated with ultimate Wilms' tumor relapse. Immunohistochemical analysis revealed that prohibitin was highly expressed in primary Wilms' tumor specimens and associated with disease stage. Using functional genetic experiments, we found that prohibitin was required for the growth and survival of Wilms' tumor cells. Overexpression of prohibitin was sufficient to block intrinsic mitochondrial apoptosis and to cause resistance to diverse chemotherapy drugs, at least in part by dysregulating factors that control apoptotic cytochrome c release from mitochondrial cristae. Thus, urine prohibitin may improve therapy stratification, noninvasive monitoring of treatment response, and early disease detection. In addition, therapeutic targeting of chemotherapy resistance induced by prohibitin dysregulation may offer improved therapies for patients with Wilms' and other relapsed or refractory tumors.
Keywords:Adolescent, Antineoplastic Combined Chemotherapy Protocols, Apoptosis, Case-Control Studies, Cohort Studies, HEK293 Cells, Kidney, Kidney Neoplasms, Local Neoplasm Recurrence, Mitochondria, Nephrectomy, Neoplasm Drug Resistance, Proteomics, RNA Interference, Repressor Proteins, Tissue Array Analysis, Transmission Microscopy Electron, Tumor Biomarkers, Tumor Cell Line, Wilms Tumor
Source:JCI Insight
Publisher:American Society for Clinical Investigation
Page Range:e127098
Date:8 August 2019
Official Publication:https://doi.org/10.1172/jci.insight.127098
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed
Related to:
https://edoc.mdc-berlin.de/18411/Preprint version

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